Patent EA-002114-B1 (EA)
Title: New farnesyl transferase inhibitors, methods for preparing thereof, pharmaceutical compositions comprising thereof and use for preparing medicaments
Inventor: BOURZAT JEAN-DOMINIQUE
IPC: A61P43/00
Filed: 1997-12-23
Abstract: 1. A compound of formula (I):   in which Ar represents a phenyl substituted by one or more halogen atoms, alkyl radical C1-C4, C1-C4 alkoxy, which can be in turn substituted by halogen atoms or a hydroxy radical; by a 3-N,N-dimethylamino or 4-N,N-dimethylamino radical; 4-methylsulfanyl radical or a cyano radical; 2,3-dihydro-1,4-benzodioxin-6-yl dihydrobenzopyran; naphtyl, or tetrahydronaphtyl, indanyl; thienyl or methylthienyl; 1,3-benzodioxol-5-yl; R represents carboxy, alkylcarboxy,alkylcarboxyoxy, alkyl, amidino,substitured by a pyridyl group or phenylsulfonyl; benzoylamidino; - R1 represents a hydrogen atom, a halogen atom, an alkyl radical, and an alkyloxy radical, wherein each of said radicals may optionally be substituted by a dialkylamino radical, wherein each of the alkyl portions of said dialkylamino radical contains 1-4 carbon atoms or may form, together with the nitrogen atom to which they are attached, a saturated heterocycle containing 5 or 6 ring members, an alkylthio radical and an alkyloxycarbonyl radical; or alternatively, situated at the ortho position with respect to one another, R1 and R2, form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen atoms, optionally substituted by a halogen atom or by an alkyl or alkyloxy radical, wherein the alkyl portions and radicals in the definition of R1 and R2 contain 1 to 4 carbon atoms; R3 represents a hydrogen atom, a halogen atom or an alkyl, hydroxy, alkyloxy, alkylcarbonyloxy, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino, dialkylamino, alkyloxycarbonylamino, carboxy, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, formyl, alkylcarbonyl, cyano, or trifluoromethyl, wherein the alkyl portions and radicals in the definition of R3 and R4 contain 1 to 4 carbon atoms; R5 represents a hydrogen atom or an alkyl or alkylthio radical, wherein for the definition of R5, the alkyl portions and radicals contain 1 to 4 carbon atoms; R2 and R4 represent a methoxy group, X represents methylene or vinyldiyl, Y represents oxygen, in a racemic form or in the form of of a single enantiomer and salts of compounds of formula (I). 2. Compounds according to claim 1, wherein when Ar represents a substituted phenyl radical, alkyl radical is methyl. 3. Compounds according to claim 1, wherein when Ar represents a substituted phenyl, alkoxy radical is methoxy radical. 4. Compounds according to claim 1, wherein when Ar represents a substituted phenyl, alkoxy radical, the alkyl portion of which is perhalogenated, is triflouromethoxy radical. 5. Compounds according to claim 1, in which R is a methylcarboxy radical. 6. Compounds according to claim 1, in which R is an amidino radical substituted by a phenylsulfonyl group. 7. Compounds according to claim 1, in which R is a benzoylamidino radical. 8. Compounds according to claim 1, in which R is an amidino radical substituted by a pyridyl group. 9. Compounds according to claim 1, in which X is vinyldiyl. 10. Compounds according to claim 1, in which Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzopyran-6-yl, 1- or 2-naphthyl, 5-indanyl or 1,2,3,4-tetrahydronaphth-6-yl radical or a phenyl radical substituted at the 4 position by a methyl, trifluoromethyl or methoxy radical. 11. Compounds according to any of claims 1 to 10, in which R is a carboxy or a methylcarboxy radical. 12. Compounds according to any of claims 1 to 11, in which Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl, 2,3-dihydrobenzofuran-5-yl or a phenyl radical substituted at the 4 position by a methyl, trifluoromethyl or methoxy radical. 13. Compounds according to any of claims 1 to 12, in which R1 is a hydrogen atom. 14. Compounds according to any of claims 1 to 13, in which R3 is a hydrogen atom. 15. Compounds according to any of claims 1 to 14, in which R5 is a hydrogen atom or a methyl radical. 16. A compound according to claim 1 wherein said compound is selected from the following compounds: methyl(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy-phenyl)propenoyl]-9-(4 -methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(3-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; methyl(3aRS,4SR,9SR,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate; (3aRS,4SR,9SR,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; 3aRS,4SR,9SR,9aRS)-3a-N-benzylcarbamoyl-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole; (3aRS,4SR,9SR,9aRS)-3a-carbamoyl-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole; benzyl(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy-phenyl)propenoyl]-9-(4 -methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-hydroxamate; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-hydroxamic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N-(3-pyridylmethyl) -carboxamide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N-(4-pyridylmethyl) -carboxamide; methyl(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-hydroxamate; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N',N'-dimethylcarboydrazide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-phenylcarbohydrazide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N', N'-pentamethylene-carbohydrazide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-3a-phenylsulphonylaminocarbonyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f] isoindole; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N-(N-oxo-3-pyridyl) methylcarboxamide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-(4-methoxyphenyl )-carbohydrazide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-methyl-N'-phenyl carbohydrazide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-(2-methylphenyl) carbohydrazide; methyl(3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindo le-3a-carboxylate; (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2 -methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2 -methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N-(3-pyridylmethyl)carboxamide; (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2 -methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N-(2-thienylmethyl)carboxamide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(3,4,5-trimethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(2-methy lphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; methyl(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4- trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4-trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4-trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N-(4-pyridylmethyl)carboxamide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4-trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-benzoylhydrazide; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4-trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-phenylhydrazide; methyl(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(2-naphthyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate; (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(2-naphthyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3